1. Field of the Invention
This invention pertains to the discovery that polypeptides that inhibit the CGRP/CGRP receptor interaction and/or antibodies and antibody fragments that specifically bind CGRP or to a CGRP receptor may be used to inhibit CGRP-induced photophobia when administered to a subject in need thereof. Polypeptides that inhibit the CGRP/CGRP receptor interaction for use in the invention include by way of example antibodies and antibody fragments specific to CGRP or the CGRP receptor and fragments or variants of CGRP or the CGRP receptor that inhibit CGRP from interacting with CGRP receptors. As photophobia is an adverse side-effect often associated with many disorders including by way of example migraine with and without aura and other headache conditions (as well as other indications disclosed infra) t these CGRP-receptor inhibitors, e.g., antibodies and antibody fragments specific to CGRP or the CGRP receptor should be well suited for inhibiting the photophobia often associated with migraine and other headache conditions as well as for treating other conditions associated with photophobia. The results also suggest that these antibodies and antibody fragments may be used to prevent the onset of photophobia in subjects in need thereof such as individuals with a chronic history of photophobia, e.g., as a result of migraine (with or without aura), other headache condition, depression, agoraphobia or other conditions prone to photophobia if the antibodies are administered prophylactically. The invention contemplates the use of these anti-CGRP antibodies and antibody fragments as a monotherapy or in therapeutic regimens with other active agents, e.g., analgesics, opioids, antidepressants or other actives dependent on the condition and the individual treated.
The invention further provides methods of screening CGRP-receptor inhibitors, e.g., anti-CGRP or anti-CGRP receptor antibodies and fragments thereof (including Fab fragments) having binding specificity to human Calcitonin Gene Related Peptide (hereinafter “CGRP”) or the CGRP receptor in specific animal models to determine the in vivo effects thereof, most especially their ability to antagonize the photophobic side effects of CGRP and to treat conditions involving photophobia including e.g., migraine.
2. Description of Related Art
Calcitonin Gene Related Peptide (CGRP) is produced as a multifunctional neuropeptide of 37 amino acids in length. Two forms of CGRP, the CGRP-alpha and CGRP-beta forms, exist in humans and have similar activities. CGRP-alpha and CGRP-beta differ by three amino acids in humans, and are derived from different genes. The CGRP family of peptides includes amylin, adrenomedullin, and calcitonin, although each has distinct receptors and biological activities. Doods, H., Curr. Op. Invest. Drugs, 2(9):1261-78 (2001).
CGRP is released from numerous tissues such as trigeminal nerves, which when activated release neuropeptides within the meninges, mediating neurogenic inflammation that is characterized by vasodilation, vessel leakage, and mast-cell degradation. Durham, P. L., New Eng. J. Med., 350 (11):1073-75 (2004). The biological effects of CGRP are mediated via the CGRP receptor (CGRP-R), which consists of a seven-transmembrane component, in conjunction with receptor-associated membrane protein (RAMP). CGRP-R further requires the activity of the receptor component protein (RCP), which is essential for an efficient coupling to adenylate cyclase through G proteins and the production of cAMP. Doods, H., Curr. Op. Invest. Drugs, 2(9):1261-78 (2001).
Migraines constitute a neurovascular disorder affecting approximately 10% of the adult population in the U.S., and are typically accompanied by intense headaches. Approximately 20-30% of migraine sufferers experience aura, comprising focal neurological phenomena that precede and/or accompany the event. CGRP is believe to play a prominent role in the development of migraines. For example, plasma concentrations of CGRP were identified elevated in jugular venous blood during the headache phase of migraines, to the exclusion of other neuropeptides. Moreover, according to Arulmozhi et al, the following has been identified in migraine sufferers: (1) a strong correlation between plasma CGRP concentrations and migraines; (2) the infusion of CGRP produced a migraine-like headache; (3) baseline CGRP levels were elevated; and (4) changes in plasma CGRP levels during migraine attacks significantly correlated with headache intensity. Arulmozhi, D. K., et al., Vas. Pharma., 43: 176-187 (2005). In addition, in the Journal of the International Association for the Study of Pain PII:S0304-3959(11)00313-7; doi:10.1016/j.pain.2011.04.033, published online 6 Jun. 2011, Hou et al., reported that keratinocyte expression of calcitonin gene-related peptide β has implications for neuropathic and inflammatory pain mechanisms.
One effective treatment for migraines is the administration of triptans, which are a family of tryptamine-based drugs, including sumatriptan and rizatriptan. Members of this family have an affinity for multiple serotonin receptors, including 5-HT1B, 5-HT1D, and 5-HT1F. Members of this family of drugs selectively constrict cerebral vessels, but also cause vasoconstrictive effects on coronary vessels. Durham, P. L., New Eng. J. Med., 350 (11):1073-75 (2004). There is a theoretical risk of coronary spasm in patients with established heart disease following administration, and cardiac events after taking triptans may rarely occur. Noted to be contraindicated for patients with coronary vascular disease.
Similarly, pain may often be addressed through the administration of certain narcotics or non-steroidal anti-inflammatory drugs (NSAIDs). However, the administration of these treatments may occur at the cost of certain negative consequences. NSAIDs have the potential to cause kidney failure, intestinal bleeding, and liver dysfunction. Narcotics have the potential to cause nausea, vomiting, impaired mental functioning, and addiction. Therefore, it is desirable to identify alternative treatments for pain in order to avoid certain of these negative consequences.
Aside from migraine, CGRP is believed to play a role in a multitude of diseases and disorders, including but not limited to other headache conditions, and pain. Due to the perceived involvement of CGRP in these diseases and disorders, there remains a need in the art for compositions and methods useful for preventing or treating diseases and disorders associated with CGRP, while avoiding adverse side effects. There in particular remains a need in the art for compositions or methods that reduce or inhibit photophobia in diseases or disorders associated with CGRP, such as migraines, headaches, and pain.
Migraineurs typically develop worsening pain and migraine symptoms when exposed to light, a phenomenon known as photophobia. Photophobia is also common in ocular disorders, such as iritis and uveitis, and intracranial disorders, such as meningitis. In the classic visual pathway, light activates rods and cones in the retina, which activate retinal ganglion cells that project via the optic nerve, to the lateral geniculate nucleus, superior colliculus, and then the visual cortex. This pathway includes image-forming and non-image-forming data. A new pathway (non-image-forming information) allows maintenance of normal circadian rhythms via the suprachiasmatic nucleus and is regulated by intrinsically photosensitive retinal ganglion cells (ipRGCs). These ipRGCs are independent of the rods and cones and contain melanopsin, a photopigment.
Noseda et al. (Noseda, R. et al. A neural mechanism for exacerbation of headache by light. Nat. Neurosci. 13, 239-245 (2010)) studied blind individuals who had migraine and correlated these findings with rat models involving tracing of ipRGC projections to areas in perception of pain from the dura. Of the blind patients with migraine, 6 had no light perception due to severe optic nerve damage or bilateral enucleation. These subjects experienced abnormal sleep patterns and poor pupillary light responses. Their migraines did not worsen with light exposure. In contrast, 14 blind subjects who were able to detect light despite minimal perception of images had normal sleep patterns and a normal pupillary light reflex. Despite widespread rod and cone degeneration, these patients had worsening migraine symptoms with light exposure during migraine attacks, suggesting that ipRGCs, and not rods and cones, are important in photophobia.
These retinal projections of non-image-forming brain areas project to the contralateral dorsocaudal region of the posterior thalamus, as demonstrated by anterograde tracing in the rat. ipRGC input to this area modulates dura-sensitive pain neurons, which also project to this region. Thalamic neurons, dually sensitive to dural pain and light input, project widely to multiple cortical regions, including the primary somatosensory cortex, the primary and secondary motor cortices, the parietal association cortex, and the primary and secondary visual cortices. These cortical projections may help explain other common migraine symptoms, in addition to photophobia, such as motor weakness or incoordination, visual disturbances, and poor concentration.
Photophobia also accompanies other less frequent but likewise disabling conditions, such as cluster headache and other trigeminal autonomic cephalalgias and blepharospasm. The mechanisms underlying photophobia involve the trigeminal system. Photophobia in blind patients suggests contributions from a nonvisual pathway. In addition, trigeminal autonomic cephalalgias, a less common group of primary headache disorders, are characterized by unilateral trigeminal-mediated pain frequently associated with ipsilateral photophobia.
Stimulation of trigeminal sensory neurons results in the release of neuropeptides (including substance P and calcitonin gene-related peptide, producing blood vessel dilation and mast cell, endothelial, and platelet activation (neurogenic inflammation), which leads to migraine. (Buzzi M G, Dimitriadou V, Theoharides T C, Moskowitz M A. 5-Hydroxytryptamine receptor agonists for the abortive treatment of vascular headaches block mast cell, endothelial and platelet activation within the rat dura mater after trigeminal stimulation. Brain Res 1992; 583:137-149). CGRP is elevated in external jugular venous blood during acute migraine pain, (Goadsby P J, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990; 28:183-187) and triptans reduce elevated CGRP levels. In animal models, mice sensitized to CGRP demonstrate more light-aversive behavior when exposed to exogenous CGRP. The administration of olcegepant, a CGRP receptor antagonist, prevented photophobia in these mice. (See Recober A, Kaiser E A, Kuburas A, Russo A F. Induction of multiple photophobic behaviors in a transgenic mouse sensitized to CGRP. Neuropharmacology 2010; 58:156-165).
However, while the use of anti-CGRP or anti-CGRP receptor antibodies and fragments to treat migraine has been suggested, to the best of Applicant's knowledge there has been no report of any polypeptide CGRP antagonist or in particular an anti-CGRP or anti-CGRP receptor antibody or antibody fragment able to alleviate or prevent the photophobic side effects of CGRP in vivo. The development of novel polypeptides that act as inhibitors of the CGRP/CGRP receptor interaction such as anti-CGRP or anti-CGRP receptor antibodies or anti-CGRP or anti-CGRP receptor antibody fragments would be beneficial for patients who either do not respond to current migraine therapeutics such as triptans or who cannot take or tolerate them because of their potential vasoconstrictive effects.